Charcot-Marie-Tooth Disease (Hereditary Motor and Sensory Neuropathy, HMSN) is a heterogeneous group of genetic disorders of peripheral nerves. The biochemical basis of these conditions is unknown. The locus of one autosomal dominant variant (HMSNIb) has been assigned to chromosome 1 by linkage to the Duffy blood group locus. The first two objectives of this study are (1) to isolate DNA from multiple large HMSNIb kindreds, sufficient to provide 80-100 informative matings, (2) to identify markers that are tightly linked to the HMSNIb locus, using recombinant DNA techniques. Linkage analysis will be performed in multiple large HMSNIb families with known gene markers from chromosome 1 including: alpha actin, alpha spectrin, amylase, amyloid P, antithrombin III, apolipoprotein AII, H4 histone, N-ras, C-reactive protein and p308. Additionally, unique sequence clones will be isolated from a chromosome 1 lambda phage library and a rodent-human hybrid containing the pericentromeric region of chromosome 1. They will be assigned to specific areas on chromosome 1 by restriction enzyme analysis of DNA from rodent-human hybrids and cell strains with structural abnormalities of chromosome 1. Clones which map to the proximal long and short arms of chromosome 1 (1p2>q2) will be screened to detect restriction fragment length polymorphisms (RFLPs), and applied to linkage studies in families with HMSNIb. A gene map in the region of the HMSNIb locus will be constructed with linkage data from studies with known gene loci and random chromosome 1 markers. (3) Objective 3 will focus on strategies to define the molecular defect(s) in HMSNIb, including high resolution chromosomal analysis and linkage and restriction mapping of cDNAs which map to the immediate area of the HMSNIb locus. Identification of DNA sequences tightly linked to HMSNIb will provide a basis for classification of different types of HMSN as well as provide insights into determining the molecular basis of this disorder. A regional gene linkage map of chromosome 1 is of general scientific interest and will provide a useful tool to study many human disorders in this region.